Perinatal lethality of Par4–/– mice delivered by primiparous dams reveals spontaneous bleeding in mice without platelet thrombin receptor function

Shauna L. French, Justin R. Hamilton

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Protease-activated receptor 4 (PAR4) is a cell surface G protein-coupled receptor for serine proteases, such as thrombin. Par4–/– mice have platelets that are unresponsive to thrombin and thereby allow examination of the importance of thrombin-induced platelet activation in (patho)physiology. Par4–/– mice are protected against arterial thrombosis but show no evidence of spontaneous bleeding. This contrasts with the bleeding experienced by mice with marked thrombocytopenia, such as those with genetic deficiency of the transcription factor, nuclear factor erythroid 2 (Nfe2–/–), that have high rates of perinatal death due to hemorrhage. Given this discrepancy in spontaneous perinatal bleeding between mice without platelets and those without thrombin-induced platelet activation mechanisms, we examined in detail the immediate postnatal survival of Par4–/– pups. We observed significant postpartum loss of Par4–/– pups derived from Par4+/– intercrosses that was restricted to a dam’s first litter; only 9% of surviving pups genotyped as Par4–/– in first litters and this normalized from the second litter onward (26%). A similar perinatal lethality in pups delivered by primiparous dams occurred in mice lacking platelets (Nfe2–/–; 10%) but not in those lacking fibrinogen (Fga–/–; 26%). These data, provide the first evidence of spontaneous bleeding in Par4–/– mice, suggest that a dam’s first litter provides a greater hemostatic challenge than subsequent litters, and uncovers an important role for platelets—and more specifically thrombin-induced platelet activation—in hemostasis during these more traumatic births.

Original languageEnglish
Pages (from-to)196-198
Number of pages3
JournalPlatelets
Volume29
Issue number2
DOIs
Publication statusPublished - 17 Feb 2018

Keywords

  • Hemostasis
  • perinatal hemorrhage
  • protease-activated receptors
  • thrombin

Cite this

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title = "Perinatal lethality of Par4–/– mice delivered by primiparous dams reveals spontaneous bleeding in mice without platelet thrombin receptor function",
abstract = "Protease-activated receptor 4 (PAR4) is a cell surface G protein-coupled receptor for serine proteases, such as thrombin. Par4–/– mice have platelets that are unresponsive to thrombin and thereby allow examination of the importance of thrombin-induced platelet activation in (patho)physiology. Par4–/– mice are protected against arterial thrombosis but show no evidence of spontaneous bleeding. This contrasts with the bleeding experienced by mice with marked thrombocytopenia, such as those with genetic deficiency of the transcription factor, nuclear factor erythroid 2 (Nfe2–/–), that have high rates of perinatal death due to hemorrhage. Given this discrepancy in spontaneous perinatal bleeding between mice without platelets and those without thrombin-induced platelet activation mechanisms, we examined in detail the immediate postnatal survival of Par4–/– pups. We observed significant postpartum loss of Par4–/– pups derived from Par4+/– intercrosses that was restricted to a dam’s first litter; only 9{\%} of surviving pups genotyped as Par4–/– in first litters and this normalized from the second litter onward (26{\%}). A similar perinatal lethality in pups delivered by primiparous dams occurred in mice lacking platelets (Nfe2–/–; 10{\%}) but not in those lacking fibrinogen (Fga–/–; 26{\%}). These data, provide the first evidence of spontaneous bleeding in Par4–/– mice, suggest that a dam’s first litter provides a greater hemostatic challenge than subsequent litters, and uncovers an important role for platelets—and more specifically thrombin-induced platelet activation—in hemostasis during these more traumatic births.",
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Perinatal lethality of Par4–/– mice delivered by primiparous dams reveals spontaneous bleeding in mice without platelet thrombin receptor function. / French, Shauna L.; Hamilton, Justin R.

In: Platelets, Vol. 29, No. 2, 17.02.2018, p. 196-198.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Perinatal lethality of Par4–/– mice delivered by primiparous dams reveals spontaneous bleeding in mice without platelet thrombin receptor function

AU - French, Shauna L.

AU - Hamilton, Justin R.

PY - 2018/2/17

Y1 - 2018/2/17

N2 - Protease-activated receptor 4 (PAR4) is a cell surface G protein-coupled receptor for serine proteases, such as thrombin. Par4–/– mice have platelets that are unresponsive to thrombin and thereby allow examination of the importance of thrombin-induced platelet activation in (patho)physiology. Par4–/– mice are protected against arterial thrombosis but show no evidence of spontaneous bleeding. This contrasts with the bleeding experienced by mice with marked thrombocytopenia, such as those with genetic deficiency of the transcription factor, nuclear factor erythroid 2 (Nfe2–/–), that have high rates of perinatal death due to hemorrhage. Given this discrepancy in spontaneous perinatal bleeding between mice without platelets and those without thrombin-induced platelet activation mechanisms, we examined in detail the immediate postnatal survival of Par4–/– pups. We observed significant postpartum loss of Par4–/– pups derived from Par4+/– intercrosses that was restricted to a dam’s first litter; only 9% of surviving pups genotyped as Par4–/– in first litters and this normalized from the second litter onward (26%). A similar perinatal lethality in pups delivered by primiparous dams occurred in mice lacking platelets (Nfe2–/–; 10%) but not in those lacking fibrinogen (Fga–/–; 26%). These data, provide the first evidence of spontaneous bleeding in Par4–/– mice, suggest that a dam’s first litter provides a greater hemostatic challenge than subsequent litters, and uncovers an important role for platelets—and more specifically thrombin-induced platelet activation—in hemostasis during these more traumatic births.

AB - Protease-activated receptor 4 (PAR4) is a cell surface G protein-coupled receptor for serine proteases, such as thrombin. Par4–/– mice have platelets that are unresponsive to thrombin and thereby allow examination of the importance of thrombin-induced platelet activation in (patho)physiology. Par4–/– mice are protected against arterial thrombosis but show no evidence of spontaneous bleeding. This contrasts with the bleeding experienced by mice with marked thrombocytopenia, such as those with genetic deficiency of the transcription factor, nuclear factor erythroid 2 (Nfe2–/–), that have high rates of perinatal death due to hemorrhage. Given this discrepancy in spontaneous perinatal bleeding between mice without platelets and those without thrombin-induced platelet activation mechanisms, we examined in detail the immediate postnatal survival of Par4–/– pups. We observed significant postpartum loss of Par4–/– pups derived from Par4+/– intercrosses that was restricted to a dam’s first litter; only 9% of surviving pups genotyped as Par4–/– in first litters and this normalized from the second litter onward (26%). A similar perinatal lethality in pups delivered by primiparous dams occurred in mice lacking platelets (Nfe2–/–; 10%) but not in those lacking fibrinogen (Fga–/–; 26%). These data, provide the first evidence of spontaneous bleeding in Par4–/– mice, suggest that a dam’s first litter provides a greater hemostatic challenge than subsequent litters, and uncovers an important role for platelets—and more specifically thrombin-induced platelet activation—in hemostasis during these more traumatic births.

KW - Hemostasis

KW - perinatal hemorrhage

KW - protease-activated receptors

KW - thrombin

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U2 - 10.1080/09537104.2017.1349310

DO - 10.1080/09537104.2017.1349310

M3 - Article

VL - 29

SP - 196

EP - 198

JO - Platelets

JF - Platelets

SN - 0953-7104

IS - 2

ER -